Labeling the human skeleton with 41Ca to assess changes in bone calcium metabolism

Bone research is limited by the methods available for detecting changes in bone metabolism. While dual X-ray absorptiometry is rather insensitive, biochemical markers are subject to significant intra-individual variation. In the study presented here, we evaluated the isotopic labeling of bone using 41Ca, a long-lived radiotracer, as an alternative approach. After successful labeling of the skeleton, changes in the systematics of urinary 41Ca excretion are expected to directly reflect changes in bone Ca metabolism. A minute amount of 41Ca (100 nCi) was administered orally to 22 postmenopausal women. Kinetics of tracer excretion were assessed by monitoring changes in urinary 41Ca/40Ca isotope ratios up to 700 days post-dosing using accelerator mass spectrometry and resonance ionization mass spectrometry. Isotopic labeling of the skeleton was evaluated by two different approaches: (i) urinary 41Ca data were fitted to an established function consisting of an exponential term and a power law term for each individual; (ii) 41Ca data were analyzed by population pharmacokinetic (NONMEM) analysis to identify a compartmental model that describes urinary 41Ca tracer kinetics. A linear three-compartment model with a central compartment and two sequential peripheral compartments was found to best fit the 41Ca data. Fits based on the use of the combined exponential/power law function describing urinary tracer excretion showed substantially higher deviations between predicted and measured values than fits based on the compartmental modeling approach. By establishing the urinary 41Ca excretion pattern using data points up to day 500 and extrapolating these curves up to day 700, it was found that the calculated 41Ca/40Ca isotope ratios in urine were significantly lower than the observed 41Ca/40Ca isotope ratios for both techniques. Compartmental analysis can overcome this limitation. By identifying relative changes in transfer rates between compartments in response to an intervention, inaccuracies in the underlying model cancel out. Changes in tracer distribution between compartments were modeled based on identified kinetic parameters. While changes in bone formation and resorption can, in principle, be assessed by monitoring urinary 41Ca excretion over the first few weeks post-dosing, assessment of an intervention effect is more reliable approximately 150 days post-dosing when excreted tracer originates mainly from bone.

The Swiss Childhood Cancer Registry: rationale, organisation and results for the years 2001-2005

QUESTIONS UNDER STUDY: Childhood cancer is a rare but severe disease. Therefore central registration of all cases is essential for surveillance and management. This paper describes the methodology and basic results of the Swiss Childhood Cancer Registry (SCCR). METHODS: The SCCR was established in 1976, originally as a national hospital-based registry of childhood malignancies. All 9 paediatric oncology-haematology clinics in Switzerland provide baseline and follow-up information on all children diagnosed with cancer. These data are registered centrally and diagnoses are coded according to the International Classification of Childhood Cancer. RESULTS: From 2001-2005, 887 cases of childhood cancer in Swiss residents under the age of 15 years were registered in the SCCR. Of these, 281 (31.7%) were leukaemias, 223 (24.0%) were CNS tumours, and 116 (13.1%) were lymphomas. The age-standardised annual incidence per 1 Million person-years (age below 15 years; world standardisation) was 154.0 (95% CI 143.7-164.3; N = 887). The incidence was higher for boys (170.2, 155.0-185.4; N = 501) than for girls (136.9, 123.0-150.8; N = 386). CONCLUSION: The close collaboration between all paediatric oncologists-haematologists in Switzerland and a university department allowed the creation of a national population-based cancer registry with detailed clinical information. The SCCR produces cancer type specific incidence and survival estimates and allows the development of nested research projects on childhood cancer aetiology, management and outcome, both on a national and on an international level.

Virtopsy, a new imaging horizon in forensic pathology: virtual autopsy by postmortem multislice computed tomography (MSCT) and magnetic resonance imaging (MRI)--a feasibility study

Using postmortem multislice computed tomography (MSCT) and magnetic resonance imaging (MRI), 40 forensic cases were examined and findings were verified by subsequent autopsy. Results were classified as follows: (I) cause of death, (II) relevant traumatological and pathological findings, (III) vital reactions, (IV) reconstruction of injuries, (V) visualization. In these 40 forensic cases, 47 partly combined causes of death were diagnosed at autopsy, 26 (55%) causes of death were found independently using only radiological image data. Radiology was superior to autopsy in revealing certain cases of cranial, skeletal, or tissue trauma. Some forensic vital reactions were diagnosed equally well or better using MSCT/MRI. Radiological imaging techniques are particularly beneficial for reconstruction and visualization of forensic cases, including the opportunity to use the data for expert witness reports, teaching, quality control, and telemedical consultation. These preliminary results, based on the concept of "virtopsy," are promising enough to introduce and evaluate these radiological techniques in forensic medicine.

Learning styles vary among general surgery residents: analysis of 12 years of data

PURPOSE: Understanding the learning styles of individuals may assist in the tailoring of an educational program to optimize learning. General surgery faculty and residents have been characterized previously as having a tendency toward particular learning styles. We seek to understand better the learning styles of general surgery residents and differences that may exist within the population. METHODS: The Kolb Learning Style Inventory was administered yearly to general surgery residents at the University of Cincinnati from 1994 to 2006. This tool allows characterization of learning styles into 4 groups: converging, accommodating, assimilating, and diverging. The converging learning style involves education by actively solving problems. The accommodating learning style uses emotion and interpersonal relationships. The assimilating learning style learns by abstract logic. The diverging learning style learns best by observation. Chi-square analysis and analysis of variance were performed to determine significance. RESULTS: Surveys from 1994 to 2006 (91 residents, 325 responses) were analyzed. The prevalent learning style was converging (185, 57%), followed by assimilating (58, 18%), accommodating (44, 14%), and diverging (38, 12%). At the PGY 1 and 2 levels, male and female residents differed in learning style, with the accommodating learning style being relatively more frequent in women and assimilating learning style more frequent in men (Table 1, p < or = 0.001, chi-square test). Interestingly, learning style did not seem to change with advancing PGY level within the program, which suggests that individual learning styles may be constant throughout residency training. If a resident's learning style changed, it tended to be to converging. In addition, no relation exists between learning style and participation in dedicated basic science training or performance on the ABSIT/SBSE. CONCLUSIONS: Our data suggests that learning style differs between male and female general surgery residents but not with PGY level or ABSIT/SBSE performance. A greater understanding of individual learning styles may allow more refinement and tailoring of surgical programs.

Increased airway smooth muscle mass in children with asthma, cystic fibrosis, and non-cystic fibrosis bronchiectasis

RATIONALE: Structural alterations to airway smooth muscle (ASM) are a feature of asthma and cystic fibrosis (CF) in adults. OBJECTIVES: We investigated whether increase in ASM mass is already present in children with chronic inflammatory lung disease. METHODS: Fiberoptic bronchoscopy was performed in 78 children (median age [IQR], 11.3 [8.5-13.8] yr): 24 with asthma, 27 with CF, 16 with non-CF bronchiectasis (BX), and 11 control children without lower respiratory tract disease. Endobronchial biopsy ASM content and myocyte number and size were quantified using stereology. MEASUREMENTS AND MAIN RESULTS: The median (IQR) volume fraction of subepithelial tissue occupied by ASM was increased in the children with asthma (0.27 [0.12-0.49]; P < 0.0001), CF (0.12 [0.06-0.21]; P < 0.01), and BX (0.16 [0.04-0.21]; P < 0.01) compared with control subjects (0.04 [0.02-0.05]). ASM content was related to bronchodilator responsiveness in the asthmatic group (r = 0.66, P < 0.01). Median (IQR) myocyte number (cells per mm(2) of reticular basement membrane) was 8,204 (5,270-11,749; P < 0.05) in children with asthma, 4,504 (2,838-8,962; not significant) in children with CF, 4,971 (3,476-10,057; not significant) in children with BX, and 1,944 (1,596-6,318) in control subjects. Mean (SD) myocyte size (mum(3)) was 3,344 (801; P < 0.01) in children with asthma, 3,264 (809; P < 0.01) in children with CF, 3,177 (873; P < 0.05) in children with BX, and 1,927 (386) in control subjects. In all disease groups, the volume fraction of ASM in subepithelial tissue was related to myocyte number (asthma: r = 0.84, P < 0.001; CF: r = 0.81, P < 0.01; BX: r = 0.95, P < 0.001), but not to myocyte size. CONCLUSIONS: Increases in ASM (both number and size) occur in children with chronic inflammatory lung diseases that include CF, asthma, and BX.

Quantification of relativistic perturbation forces on spacecraft trajectories

The intent of the work presented in this thesis is to show that relativistic perturbations should be considered in the same manner as well known perturbations currently taken into account in planet-satellite systems. It is also the aim of this research to show that relativistic perturbations are comparable to standard perturbations in speciffc force magnitude and effects. This work would have been regarded as little more then a curiosity to most engineers until recent advancements in space propulsion methods { e.g. the creation of a artiffcial neutron stars, light sails, and continuous propulsion techniques. These cutting-edge technologies have the potential to thrust the human race into interstellar, and hopefully intergalactic, travel in the not so distant future. The relativistic perturbations were simulated on two orbit cases: (1) a general orbit and (2) a Molniya type orbit. The simulations were completed using Matlab's ODE45 integration scheme. The methods used to organize, execute, and analyze these simulations are explained in detail. The results of the simulations are presented in graphical and statistical form. The simulation data reveals that the speciffc forces that arise from the relativistic perturbations do manifest as variations in the classical orbital elements. It is also apparent from the simulated data that the speciffc forces do exhibit similar magnitudes and effects that materialize from commonly considered perturbations that are used in trajectory design, optimization, and maintenance. Due to the similarities in behavior of relativistic versus non-relativistic perturbations, a case is made for the development of a fully relativistic formulation for the trajectory design and trajectory optimization problems. This new framework would afford the possibility of illuminating new more optimal solutions to the aforementioned problems that do not arise in current formulations. This type of reformulation has already showed promise when the previously unknown Space Superhighways arose as a optimal solution when classical astrodynamics was reformulated using geometric mechanics.

Specific roles of Rac1 and Rac2 in motile functions of HT1080 fibrosarcoma cells

Rho family proteins are constitutively activated in the highly invasive human fibrosarcoma HT1080 cells. We now investigated the specific roles of Rac1 and Rac2 in regulating morphology, F-actin organization, adhesion, migration, and chemotaxis of HT1080 cells. Downregulation of Rac1 using specific siRNA probes resulted in cell rounding, markedly decreased spreading, adhesion, and chemotaxis of HT1080 cells. 2D migration on laminin-coated surfaces in contrast was not markedly affected. Selective Rac2 depletion did not affect cell morphology, cell adhesion, and 2D migration, but significantly reduced chemotaxis. Downregulation of both Rac1 and Rac2 resulted in an even more marked reduction, but not complete abolishment, of chemotaxis indicating distinct as well as overlapping roles of both proteins in chemotaxis. Rac1 thus is selectively required for HT1080 cell spreading and adhesion whereas Rac1 and Rac2 are both required for efficient chemotaxis.

Different patterns of Siglec-9-mediated neutrophil death responses in septic shock

Sialic-acid-binding immunoglobulin-like lectin (Siglec) 9 mediates death signals in neutrophils. The objective of this study was to determine the heterogeneity of neutrophil death responses in septic shock patients and to analyze whether these ex vivo data are related to the severity and outcome of septic shock. In this prospective cohort study, blood samples of patients with septic shock (n = 26) in a medical-surgical intensive care unit (ICU) were taken within 24 h of starting the treatment of septic shock (phase A), after circulatory stabilization (phase B), and 10 days after admission or at ICU discharge if earlier (phase C). Neutrophil death was quantified in the presence and absence of an agonistic anti-Siglec-9 antibody after 24 h ex vivo. In phase A, two distinct patterns of Siglec-9-mediated neutrophil death were observed: resistance to neutrophil death (n = 14; Siglec-9 nonresponders) and increased neutrophil death (n = 12; Siglec-9 responders) after Siglec-9 ligation compared with neutrophils from normal donors. Experiments using a pharmacological pan-caspase-inhibitor provided evidence for caspase-independent neutrophil death in Siglec-9 responders upon Siglec-9 ligation. There were no differences between Siglec-9 responders and nonresponders in length of ICU or hospital stay of survivors or severity of organ dysfunction. Taken together, septic shock patients exhibit different ex vivo death responses of blood neutrophils after Siglec-9 ligation early in shock. Both the resistance and the increased susceptibility to Siglec-9-mediated neutrophil death tend to normalize within 72 h after shock. Further studies are required to understand the role of Siglec-9-mediated neutrophil death in septic shock.